The pathological misfolding and aggregation of soluble α-synuclein into toxic oligomers and insoluble amyloid fibrils causes Parkinson’s disease, a progressive age-related neurodegenerative disease for which there is no cure. HET-s is a soluble fungal protein that can form assembled amyloid fibrils in its prion state. We engineered HET-s(218-298) to form four different fibrillar vaccine candidates, each displaying a specific conformational epitope present on the surface of α-synuclein fibrils. Vaccination with these four vaccine candidates prolonged the survival of immunized TgM83+/− mice challenged with α-synuclein fibrils by 8% when injected into the brain to model brain-first Parkinson’s disease or by 21% and 22% when injected into the peritoneum or gut wall to model body-first Parkinson’s disease. Antibodies from fully immunized mice recognized α-synuclein fibrils and brain homogenates from patients with Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Conformation-specific vaccines that mimic epitopes present only on the surface of pathological fibrils but not on soluble monomers, hold great promise for protection against Parkinson’s disease, related synucleinopathies, and other amyloidogenic protein misfolding disorders.

中文翻译：

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使用结构适应的真菌蛋白原纤维进行疫苗接种可诱导对帕金森病的免疫力

可溶性 α-突触核蛋白的病理性错误折叠和聚集成有毒寡聚物和不溶性淀粉样原纤维会导致帕金森病，这是一种与年龄相关的进行性神经退行性疾病，无法治愈。HET-s 是一种可溶性真菌蛋白，可以在朊病毒状态下形成组装的淀粉样原纤维。我们对 HET-s(218-298) 进行了改造，形成了四种不同的纤维状疫苗候选物，每种都显示了 α-突触核蛋白原纤维表面上存在的特定构象表位。使用这四种候选疫苗进行疫苗接种，将接受 α-突触核蛋白原纤维攻击的免疫 TgM83+/- 小鼠的存活率延长了 8%（当注射到大脑中以模拟脑优先帕金森病时），或者当注射到腹膜或肠道时分别延长了 21% 和 22%墙壁来模拟身体优先的帕金森病。完全免疫小鼠的抗体可识别帕金森病、路易体痴呆和多系统萎缩患者的 α-突触核蛋白原纤维和脑匀浆。模仿仅存在于病理原纤维表面而不是可溶性单体上的表位的构象特异性疫苗对于预防帕金森病、相关突触核蛋白病和其他淀粉样蛋白错误折叠疾病具有很大的希望。